The present invention relates to a series of novel griseolic derivatives and provides methods of using them and compositions containing them.
Griseolic acid is a nucleoside-type compound having an adenine base and two carboxylic acid groups. It was first disclosed in, inter alia, European patent specification No. 29,329A, but its structure was not, at that stage, known. Its structure was first disclosed in U.S. Pat. No. 4,460,765 (assigned to the present assignees) and published after the priority hereof.
The structure of griseolic acid may be represented by the formula: ##STR3##
It should be noted that natural griseolic acid, being a product of natural biosynthesis, is synthesized stereospecifically. In fact, at both the 2' and the 7' positions, it is in the R-configuration.
In accordance with the recommendations of the International Union of Pure and Applied Chemistry (I.U.P.A.C.), the compounds of the present invention are named as derivatives of griseolic acid, taking griseolic acid as the parent structure. The numbering system employed herein is that shown on the above formula of griseolic acid.
In naming specific compounds of the present invention in accordance with this convention, substituents at the 2' and 7' positions are assumed to be in the R-configuration (like natural griseolic acid) unless the contrary is stated.
Griseolic acid, as well as the derivatives of the present invention, has the ability to inhibit the activity of cyclic adenosine monophosphate (cAMP) phosphodiesterase (PDE) and can thus increase the level of cAMP in the cells of a patient treated with it.
It is well-known that cAMP, which is very widely distributed in animal tissues, functions as a second messenger for and mediates the effect of a large number of hormones; as a result, cAMP has a variety of very important physiological and biochemical roles. Additionally, it is known to have an effect on or participate in: division, growth and differentiation of cells; systole; haemapoiesis; various activities of the central nervous system; immune reactions; and liberation of insulin and histamine. Its concentration in tissues, and hence its effect on these various functions, depends upon the balance between the enzyme which synthesizes cAMP (adenylate cyclase) and the enzyme which decomposes cAMP PDE. An inhibitor against cAMP PDE would increase the level of cAMP in the cells and would thus be a value as an angiocardiokinetic agent, an antiasthmatic agent, a smooth muscle relaxant, a psychotropic or neurotropic agent, an anti-inflammatory agent, an anti-cancer agent and a treatment for diabetes.
Griseolic acid has been demonstrated to have the range of biochemical activities described in the preceding paragraph and we have now discovered a series of novel derivatives of griseolic acid which likewise have these activities but which have a surprisingly low toxicity. In particular, the compounds of the invention have been found to improve brain metabolism substantially, to potentiate the effect of known anti-cancer agents and to potentiate the effect of insulin. Moreover, the compounds of the invention have been found to improve blood viscosity.